The present invention relates to novel quinuclidine derivatives, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists. This invention also relates to novel intermediates used in the synthesis of such substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals (having originally been isolated from gut) and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
In the recent past, some attempts have been made to provide antagonists for substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases listed above. The few such antagonists thus far described are generally peptide-like in nature and are therefore too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease. The non-peptidic antagonists of the present invention, on the other hand, do not possess this drawback, being far more stable from a metabolic point of view than the agents referred to above.
The quinuclidine derivatives of this invention are referred to generically in PCT patent application PCT/US 89/05338, filed Nov. 20, 1989 and U.S. Pat. application Ser. No. 557,442, filed Jul. 23, 1990, both of which are assigned in common with the present application. Other quinuclidine derivatives that exhibit activity as substance P receptor antagonists are referred to in PCT patent application PCT/US 91/02853, entitled "3-Amino-2-Aryl Quinuclidines" and filed on Apr. 25, 1991 and in PCT patent application PCT/US 92/03369, entitled "Quinuclidine Derivatives" and filed on May 14, 1991. These applications are also assigned in common with the present application.
Piperidine derivatives and related heterocyclic nitrogen containing compounds that are useful as substance P antagonists are referred to in U.S. Pat. application Ser. No. 619,361, filed Nov. 28, 1990 and U.S. Pat. application Ser. No. 590,423, filed Sep. 28, 1990, both of which are assigned in common with the present application.